Stem cell marker (Nanog) and Stat-3 signaling promote MicroRNA-21 expression and chemoresistance in hyaluronan/CD44-activated head and neck squamous cell carcinoma cells
| Autor: | Christina C. Spevak, Lilly Y.W. Bourguignon, Gabriel Wong, Christine Earle, Katherine C. Krueger |
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| Rok vydání: | 2011 |
| Předmět: |
Cancer Research
Drug Resistance Stem cell marker Nanog 0302 clinical medicine CD44 Hyaluronic Acid 0303 health sciences Tumor biology Nanog Homeobox Protein Hyaluronan Receptors Head and Neck Neoplasms 030220 oncology & carcinogenesis Carcinoma Squamous Cell miR-21 Signal transduction Signal Transduction STAT3 Transcription Factor Homeobox protein NANOG head & neck cancer Clinical Sciences Oncology and Carcinogenesis Article Cell Line Promoter Regions hyaluronan 03 medical and health sciences Genetic Downregulation and upregulation microRNA Genetics medicine Humans Oncology & Carcinogenesis Antigens Molecular Biology 030304 developmental biology Cell Nucleus nanog Homeodomain Proteins Carcinoma Stat-3 medicine.disease Head and neck squamous-cell carcinoma MicroRNAs Squamous Cell Drug Resistance Neoplasm biology.protein Cancer research Neoplasm |
| Zdroj: | Oncogene Oncogene, vol 31, iss 2 |
| ISSN: | 1476-5594 0950-9232 |
| Popis: | MicroRNAs are often associated with the pathogenesis of many cancers including Head and Neck Squamous Cell Carcinoma (HNSCC). In particular, microRNA-21 (miR-21) appears to play a critical role in tumor cell survival, chemoresistance and HNSCC progression. In this study we investigated matrix hyaluronan (HA)-induced CD44 (a primary HA receptor) interaction with the stem cell markers, Nanog and Stat-3, in HNSCC cells (HSC-3 cells). Our results indicate that HA binding to CD44 promotes Nanog-Stat-3 (also tyrosine phosphorylated Stat-3) complex formation, nuclear translocation and transcriptional activation. Further analyses reveal that miR-21 is controlled by an upstream promoter containing Stat-3 binding site(s), while chromatin immunoprecipitation (ChIP) assays demonstrate that stimulation of miR-21 expression by HA/CD44 signaling is Nanog/Stat-3-dependent in HNSCC cells. This process results in a decrease of a tumor suppressor protein (PDCD4), and an upregulation of inhibitors of the apoptosis family of proteins (IAPs) as well as chemoresistance in HSC-3 cells. Treatment of HSC-3 cells with Nanog- and/or Stat-3-specific small interfering RNAs (siRNAs) effectively blocks HA-mediated Nanog-Stat-3 signaling events, abrogates miR-21 production and increases PDCD4 expression. Subsequently, this Nanog-Stat-3 signaling inhibition causes downregulation of survival protein (IAP) expression and enhancement of chemosensitivity. To further evaluate the role of miR-21 in tumor cell-specific functions, HSC-3 cells were also transfected with a specific anti-miR-21 inhibitor in order to silence miR-21 expression and block its target functions. Our results demonstrate that anti-miR-21 inhibitor not only upregulates PDCD4 expression, but also decreases IAP expression and enhances chemosensitivity in HA-treated HNSCC cells. Together, these findings indicate that the HA-induced CD44 interaction with Nanog and Stat-3 plays a pivotal role in miR-21 production leading to PDCD4 reduction, IAP upregulation and chemoresistance in HNSCC cells. This novel Nanog/Stat-3 signaling pathway-specific mechanism involved in miR-21 production is significant for the formation of future intervention strategies in the treatment of HA/CD44-activated HNSCC. |
| Databáze: | OpenAIRE |
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